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Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht 3584 CX, The Netherlands.
Human Molecular Genetics (Impact Factor: 6.68). 05/2012; 21(17):3776-84. DOI: 10.1093/hmg/dds199
Source: PubMed

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees
affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex
inheritance of risk variants in multiple genes. Therefore, we screened 111 familial ALS (FALS) patients from 97 families,
and large cohorts of sporadic ALS (SALS) patients and control subjects for mutations in TAR DNA-binding protein (TARDBP), fused in sarcoma/translated in liposarcoma (FUS/TLS), superoxide dismutase-1 (SOD1), angiogenin (ANG) and chromosome 9 open reading frame 72 (C9orf72). Mutations were identified in 48% of FALS families, 8% of SALS patients and 0.5% of control subjects. In five of the FALS
families, we identified multiple mutations in ALS-associated genes. We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations. Statistical analysis demonstrated that the presence of multiple mutations in FALS is in excess of what is to be
expected by chance (P = 1.57 × 10−7). The most compelling evidence for an oligogenic basis was found in individuals with a p.N352S mutation in TARDBP, detected in five FALS families and three apparently SALS patients. Genealogical and haplotype analyses revealed that these
individuals shared a common ancestor. We obtained DNA of 14 patients with this TARDBP mutation, 50% of whom had an additional mutation (ANG, C9orf72 or homozygous TARDBP). Hereby, we provide evidence for an oligogenic aetiology of ALS. This may have important implications for the interpretation
of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of
unaffected family members.

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    • "An imperfect hexanucleotide expansion and a single base pair substitution were identified in the 5′UTR region of two index cases, which were both predicted to be pathogenic . Although both of these cases were also positive for a C9orf72 expansion mutation, the co-existence of multiple mutations, including C9orf72 and TARDBP, has been reported previously in ALS [12]. In addition , the 7 repeat was found in a sporadic ALS case that did not carry a C9orf72 hexanucleotide expansion. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of the Neurological Sciences 01/2015; 349(1-2). DOI:10.1016/j.jns.2015.01.021 · 2.26 Impact Factor
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    • "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by degeneration of both lower and upper motor neurons. Genetic factors, including mutations of the C9orf72, SOD1 (superoxide dismutase 1), TARDPB, or FUS (fused in sarcoma) genes, may explain almost 50% of familial cases (FALS) [1]. The etiology of this adult-onset motor neuron disease remains unknown for many sporadic cases (SALS). "
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    • "Several TARDBP variants have been identified in both control and patient populations. These include the missense p.A90V [Chiang et al., 2012; Kabashi et al., 2008; Van Blitterswijk et al., 2012b; Winton et al., 2008] and the p.D65E identified in an African nonaffected control [Guerreiro et al., 2008]. A number of synonymous changes have been identified (p.N12N, p.P19P, p.L27L, p.A66A, p.S104S, p.K137K, p.P225P, p.A321A, p.N352N, p.A366A) as well different intronic variants. "
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